The perception that nitric oxide (NO), a chemically active gas, plays an essential role in human and animal physiology was first demonstrated in 1987 with the publication of Nitric Oxide Accounts for the Biological Activity of Endothelium Derived Relaxing Factor; Palmer, R. M., Ferridge, A. G., Moncada, S; Nature 1987; 327:524-526. The authors demonstrated that the endothelial-derived relaxation factor (EDRF) was indeed nitric oxide. Many research publications have since defined more clearly the multiple and complex roles of NO in human, animal and plant physiology. Synthesized endogenously in humans, animals and plants, NO plays many very important physiological roles. For example, research reports have shown that NO may be effective in the treatment of sickle cell anemia.
Nitric oxide, in conjunction with ventilatory support and other appropriate agents, is used for the treatment of term and near-term (greater than 34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation. It has also been reported to be useful as a selective pulmonary vasodilator in patients with adult respiratory distress syndrome. Lack of systemic vasodilatory effects with nitric oxide is an advantage over other vasodilators (e.g., epoprostenol (prostacyclin), nitroprusside).
Among the increasing range of pathologies which can be successfully treated with gaseous NO is anal disease. Anal fissure (or fissure-in-ano), anal ulcer, acute hemorrhoidal disease, and levator spasm (proctalgia fugax) are common, benign conditions of the anal canal which affect men and women. An anal fissure or ulcer is a tear or ulcer of the mucosa or lining tissue of the distal anal canal. An anal fissure/ulcer can be associated with other systemic or local diseases, but it is more frequently present as an isolated finding. The typical, idiopathic fissure or ulcer is confined to the anal mucosa, and usually lies in the posterior midline, distal to the dentate line. The person with an anal fissure or ulcer suffers from anal pain and bleeding, more pronounced during and after bowel movements.
Hemorrhoids are specialized vascular areas lying subjacent to the anal mucosa. Symptomatic hemorrhoidal disease is manifest by bleeding, thrombosis or prolapse of the hemorrhoidal tissues. Men and women are affected. Most commonly, internal hemorrhoidal tissue bulges into the anal canal during defecation causing bleeding. As the tissue enlarges, prolapse pain, thrombosis, and bleeding can ensue. Thrombosis of internal or external hemorrhoids is another cause of pain and bleeding.
Levator spasm (or proctalgia fugax) is a condition of unknown etiology affecting women more frequently than men. This syndrome is characterized by spasticity of the levator ani muscle, a portion of the anal sphincter complex. The patient suffering from levator spasm complains of severe, episodic rectal pain. Physical exam may reveal spasm of the puborectalis muscle. Pain may be reproduced by direct pressure on this muscle. Bleeding is not associated with this condition.
The underlying causes of these problems are poorly understood. However, all of these disorders are associated with a relative or absolute degree of anal sphincter hypertonicity. In the case of anal fissure/ulcer the abnormality appears to be an as yet unidentified problem of the internal and sphincter muscle. The internal sphincter is a specialized, involuntary muscle arising from the inner circular muscular layer of the rectum. Intra-anal pressure measurements obtained from people suffering from typical anal fissure/ulcer disease show an exaggerated pressure response to a variety of stimuli. The abnormally high intra-anal pressure is generated by the internal sphincter muscle. The abnormally elevated intra-anal pressure is responsible for non-healing of the fissure/ulcer and the associated pain. U.S. Pat. No. 5,504,117 teaches methods to treat anal pathologies by the topical application of preparations that stimulate the production of endogenous nitric oxide synthase (NOS) which, in turn, causes NO to be generated in endothelial tissue and in the nervous system, by the catalytic action of NOS upon L-Argenine.
Although safe NO dosage values are at present still evolving, the Occupational Safety and Health Administration (OSHA) has set the time-weighted average inhalation limit for NO at 25 ppm for 10 hours and NOsub2 not to exceed 5 ppm. NIOSH Recommendations for Occupational Safety and Health Standards: Morbidity and Mortality Weekly Report, Vol. 37, No. S-7, p. 21(1988). The Environmental Protection Agency (EPA) has stated that a health-based national (maximum ambient) air quality standard for NOsub2 is 0.053 ppm (measured as an annual average).
When exposed to oxygen, NO gas will, depending on environmental conditions, undergo oxidation to NOsub2, also to higher oxides of nitrogen. Gaseous nitrogen dioxide, if inhaled in sufficient concentration (for example, as little as 10 ppm for ten minutes), is toxic to lung tissue and can produce pulmonary edema and this concentration and exposure time, or more, could result in death. Standards with regard to nitrogen dioxide toxicity have not been firmly established. Nitrogen dioxide is a deep lung irritant that can produce pulmonary edema and death if inhaled at high concentrations. The effects of NOsub2 depend on the level and duration of exposure. Exposure to moderate NOsub2 levels, 50 ppm for example, may produce cough, hemoptysis, dyspnea, and chest pain. Exposure to higher concentrations of NOsub2 (greater than 100 ppm) can produce pulmonary edema, that may be fatal or may lead to bronchiolitis obliterans. Some studies suggest that chronic exposure to nitrogen dioxide may predispose to the development of chronic lung diseases, including infection and chronic obstructive pulmonary diseases.
It is common practice in therapeutic NO inhalation procedures both to monitor and also to remove NOsub2 before it can be inhaled by a subject to whom NO is being applied. For example, the NO respiratory gas mixture may be transported through a soda lime mixture to scavenge nitrogen dioxide. However, NO gas in the therapeutic concentration range (i.e. 1 ppm to as much as 100 ppm) can be administered safely, for short time periods, in dry normal air (21% oxygen) without the formation of toxic concentrations of NOsub2. Moreover, the present invention may include intra-capsular means to adsorb NOsub2.
Historically, NO gas is commercially manufactured using the Ostwald process (U.S. Pat. Nos. 4,774,069, 5,478,549) in which ammonia is catalytically converted to NO and Nitrous Oxide at a temperature above 800 degrees centigrade. This process thus involves the mass production of NO at high temperatures in an industrial setting. The therapeutic advantages of NO over other pulmonary and cardiovascular drugs have led researchers to attempt the design of an instrument that can deliver variable concentrations of NO accurately. For example, U.S. Pat. No. 5,396,882 describes a process for generating NO in an electric arc discharge in air where the electrodes are separated by an air gap in an arc chamber. The application of a high voltage across the air gap produces a localized plasma that breaks down oxygen and nitrogen molecules and generates a mixture of NO, ozone, and other NOx species. The concentration of NO in this system can be varied by adjusting the operating current. The gas mixture is then purified and mixed with air in order to obtain therapeutically significant concentrations of NO prior to administration to a patient. However, the quantification of generated NO by this system is purely empirical making the instrument extremely susceptible to the slightest fluctuations in the internal and external parameters such as ambient humidity and the surface area of the electrodes in the arc chamber.
Although inhalation of nitric oxide gas has been shown to be effective for treatment of pulmonary hypertension, there are several drawbacks and limitations of this particular mode of therapy. For example, current art therapy requires large and heavy gas tanks, expensive monitoring equipment, and a trained anesthesiologist to operate the tanks and equipment so as to deliver NO gas to a patient with safety. Therefore, NO inhalation therapy is at present limited to hospitals or similar clinical facilities. Thus there is a great needed for a more flexible, portable and less expensive means with which NO may be delivered safely in an organ specific manner without causing systemic vasodilation.
For over a century, nitroglycerin has been used as a vasodilating agent in the treatment of cardiovascular disease. Nitroglycerin, or glyceryl trinitrate, is an organic nitrate ester which when administered to a subject is converted biologically to nitric oxide by stimulating an enzyme, nitric oxide synthase (NOS), which in turn, catalyzes the production of endogenous NO from L-argenine. However, the effectiveness of nitroglycerin is greatly diminished because the recipient of therapeutic administration of nitroglycerin rapidly develops a tolerance to the beneficial effects of nitroglycerin. Therefore, onset of nitroglycerin tolerance significantly limits the therapeutic value of nitroglycerin because increased nitroglycerin dosages have little or no effect on vasorelaxation or vasodilatation. A further limitation may result from the fact that nitroglycerin is physiologically non specific. That is, vascular response to the drug will be generally distributed over the entire circulatory system.
The present invention teaches new and novel methods and means with which NO can be rapidly delivered to alveolar vascular tissue so as to bring about a rapid increase in the concentration of NO in lung and heart vascular epithelia. The effect is to cause rapid dilation of blood vessels in the lung and heart and to a considerably lesser degree, in more distal blood vessels through which blood circulates owing to the rapid absorption of NO by red blood cells.
The present invention features methods for prevention and treatment of asthma attacks and other forms of bronchial constriction, acute respiratory failure, or reversible pulmonary vasoconstriction (i.e., acute or chronic pulmonary vasoconstriction which has a reversible component). An affected subject may be identified, for example, by acute physical distress symptoms or by traditional diagnostic procedures. The subject will then inhale a therapeutically-effective concentration of gaseous nitric oxide so as to achieve therapeutic relief.
The present invention teaches methods and devices that produce NO from the inside of portable and disposable capsules containing NO under pressure and from chemical reagents which, when appropriately combined or activated, generate a controlled outflow of pure NO gas to the capsule exterior in free air. It is essential that the concentration of gas inhaled from the above mentioned capsular NO source be large enough to effect therapeutically beneficial results and at the same time not exceed a safe NO concentration maximum for gas inhalation. Both exposure time and gas concentration values together dictate what safe dosage may be.
The present invention teaches the principles of new devices and new procedures that will provide effective therapeutic application of inhaled NO during coronary and respiratory emergencies such as angina, thrombosis in heart and lung blood vessels; also hypertension in lung vasculature, as well as reversible asthma attacks.